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Impact of Systematic Isolation of Superior Vena Cava in Addition to Pulmonary Vein Antrum Isolation on the Outcome of Paroxysmal, Persistent, and Permanent Atrial Fibrillation Ablation: Results from a Randomized Study ANDREA CORRADO, M.D.,∗ ALDO BONSO, M.D.,∗ MICHELA MADALOSSO, M.D.,∗ ANTONIO ROSSILLO, M.D.,∗ SAKIS THEMISTOCLAKIS, M.D.,∗ LUIGI DI BIASE, M.D.,†,‡ ANDREA NATALE, M.D.,† and ANTONIO RAVIELE, M.D.∗ From the ∗ Cardiovascular Department, “Dell’Angelo” Hospital, Mestre, Venezia, Italy; †Texas Cardiac Arrhythmia Institute, St. David’s Medical Center, Austin, Texas, USA; and ‡Department of Cardiology, University of Foggia, Foggia, Italy

Impact of the Systematic Isolation of the Superior Vena Cava. Background: Pulmonary veins (PVs) have been shown to represent the most frequent sites of ectopic beats initiating paroxysmal atrial fibrillation (AF). However, additional non-PV triggers, arising from different areas, have been reported as well. One of the most common non-PV sites described is the superior vena cava. Aims: The purpose of the study was to investigate the impact resulting from the systematic isolation of the superior vena cava (SVCI) in addition to pulmonary vein antrum isolation (PVAI) on the outcome of paroxysmal, persistent, and permanent AF ablation. Methods: A total of 320 consecutive patients who had been referred to our center in order to undergo a first attempt of AF ablation were randomized into 2 groups. Group I (160 patients) underwent PVAI only; Group II (160 patients) underwent PVAI and SVCI. Results: AF was paroxysmal in 134 (46%), persistent in 75 (23%), and permanent in 111 (31%) of said patients. SVCI was performed on 134 of the 160 patients (84%) in Group II. SVC isolation was not performed on the remaining 26 patients either because of phrenic nerve capture or the lack of SVC potentials. Comparison of the outcome data between the 2 groups, after a follow-up of 12 months, revealed a significant difference in total procedural success solely with patients manifesting paroxysmal atrial fibrillation (56/73 [77%] Group I vs. 55/61 [90%] Group II; P = 0.04; OR 2.78). Conclusions: In our study, the strategy of the empiric SVCI in addition to PVAI has improved the outcome of AF ablation solely in patients manifesting paroxysmal AF. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1-5, January 2010) atrial fibrillation, catheter ablation, superior vena cava, pulmonary vein isolation Introduction Pulmonary veins (PVs) have been demonstrated to be the most frequent sites of ectopic beats initiating paroxysmal atrial fibrillation (AF).1,2 Several studies have evaluated pulmonary vein isolation (PVI) as the treatment strategy for AF.3,4 However, other foci have been described, arising from different areas, such as superior vena cava (SVC), coronary sinus, persistent left superior vena cava, vein of Marshall, left atrial posterior wall, interatrial septum, and crista terminalis.5-9 Recurrences of AF, despite complete PV disconnection, suggest an important possible role of these foci. Until Dr. Natale reports participation in a research grant supported by St. Jude Medical, compensation for participation in speaker’s bureaus from St. Jude Medical, Biosense Webster, Medtronic, and Boston Scientific, and serving on the advisory board of Biosense Webster. No other conflicts were declared. Address for correspondence: Andrea Corrado, M.D., Cardiovascular Department, “Dell’Angelo” Hospital, 30174 Mestre, Venice, Italy. Fax: +390419657235; E-mail: [email protected] Manuscript received 6 November 2008; Revised manuscript received 30 June 2009; Accepted for publication 7 July 2009. doi: 10.1111/j.1540-8167.2009.01577.x

now, only limited data concerning the outcome of adjunctive catheter ablation of these areas have been available. The aim of this prospective randomized study was to assess adjunctive success rate, outcome, and complications of the systematic empiric electrical isolation of the superior vena cava (SVCI) in addition to pulmonary vein antrum isolation (PVAI). Methods Patient Population We collected data from 320 consecutive patients who had been referred to our center for catheter ablation of symptomatic AF refractory to at least 1 antiarrhythmic drug (AAD) between January 2004 and May 2006. Before the ablation procedure, all patients gave their written informed consent, as approved by the institutional ethics committee, and patients’ data were collected in accordance with institutional ethics guidelines. Patients who had undergone a previous AF ablation were duly excluded from the study. Preablation Management Prior to ablation, patients underwent standard examinations and oral anticoagulation therapy. Antiarrhythmic drugs were withdrawn 4–5 half-lives prior to the procedure

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and amiodarone 4–5 months before. Warfarin was terminated 2–5 days before the ablation and bridge with low-molecular-weight heparin was initiated. If patients were in AF on the day of the procedure, a transesophageal echocardiography was performed in order to exclude the presence of a thrombus. Ablation Procedure Patients were prospectively randomized for 1 of the 2 ablation strategies: PVAI (Group I, n = 160) or PVAI + SVCI (Group II, n = 160). Randomization was performed by a computer-generated randomization scheme. Group I (PVAI) In this group, ablation strategy included PVAI guided by circular mapping catheter and intracardiac echocardiography (ICE). The details of the ablation procedure have been presented elsewhere.10 Briefly, after double transseptal puncture performed under ICE guidance, a circular mapping catheter (Lasso, Biosense Webster, Diamond Bar, CA, USA) and an 8mm radiofrequency ablation catheter (Celsius DS, Biosense Webster) were advanced into the left atrium. A 10-Fr 64element phased-array ultrasound-imaging catheter (AcuNav, Acuson Inc., Mountain View, CA, USA) was used to identify the antra of PVs and to guide sequential placement of the circular mapping catheter along the complete circumference of each PV antrum. Radiofrequency ablation was performed whenever PV potentials were recorded with the circular mapping catheter around the PV antra. The starting power was 60 watts, which was titrated down by 5-watt decrements if microbubbles were seen.10,11 The endpoint of ablation was the complete electrical disconnection of all PV antra from the left atrium. During the procedure, heparin was administered to achieve an activated coagulation time (ACT) above 350 seconds. At the end of all procedures, patients were given 325 mg of aspirin, before leaving the EP laboratory. Group II (PVAI + SVCI) In this group, SVCI guided by a circular mapping catheter and ICE were performed, in addition to PVAI. The circular mapping catheter was placed above the junction between the right atrium and SVC at the level of the lower border of the pulmonary artery guided by intracardiac echocardiography (Fig. 1). RF was delivered at 50 watts, 60◦ . Before RF delivery, output pacing (30 mA) was performed at any site of the posterolateral side of the SVC. If diaphragmatic stimulation was present, ablation in this site was not performed in order to avoid injury to the phrenic nerve. The endpoint of ablation was to eliminate any potential along the mapping cathether (Fig. 2A,B). Postablation Follow-Up All patients were monitored while at the hospital, overnight, and were usually discharged on the day following the procedure. Oral anticoagulation with warfarin was restarted on all patients the same evening following the ablation procedure. Low-molecular-weight heparin was administered twice a day until the international normalized ratio (INR) reached ≥ 2.0. All the patients were discharged without AADs. Transthoracic echocardiography and spiral computed tomography scans were performed at the 3-month

Figure 1. Intracardiac view of superior vena cava isolation. Ablations sites were determined placing the circular mapping catheter (MC) above the junction between the right atrium and superior vena cava (SVC) at the level of the lower border of the right pulmonary artery (RPA) guided by intracardiac echocardiography.

follow-up to evaluate the atrial function and patency of the pulmonary veins. If the left atrial mechanical function and PV patency proved normal, and patients were free from AF, warfarin was discontinued. All patients were followed for 12 months after ablation. During this time they were examined in the outpatient clinic at the 1, 3, 6, 9, and 12 months. Data were collected prospectively during the followup visit by the same team of physicians that had performed the procedures. The documentation of arrhythmic episodes was based on ECG and/or Holter data. A 48-hour Holter recording was scheduled routinely on all patients within 1 month of the procedure and at every follow-up examination. In addition, patients were advised to refer as soon as possible to the clinic symptoms compatible with arrhythmias, at which point an ECG and a 48-hour Holter monitoring was performed. If symptoms were not clarified by these exams, they were supplied with a transtelephonic rhythm transmitter, and were asked to transmit their rhythm every time they had symptoms. The interrogation of implanted devices was also used (when available) to confirm arrhythmia recurrence. An AF recurrence was defined as an episodic AF longer than 30 seconds. Recurrences taking place within the first 8 weeks of ablation (blanking period) were not considered failure of the AF ablation while, conversely, any such recurrence after 8 weeks was considered a procedural failure. Statistical Analysis Continuous variables were expressed as mean ± SD values and compared by Student t-test. The differences among groups were analyzed by using the chi-square test for nonparametric variables. Statistical significance was considered at a P value < 0.05. Results No statistically significant differences in terms of baseline variables were found between the 2 groups (Table 1).

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Figure 2. A: Superior vena cava and atrial potentials (SVCp and Ap) recorded by the circular mapping catheter (MC) before the isolation of the SVC. B: Atrial potential (Ap) recorded by the MC after the isolation of the SVC.

Success Rate of Ablation Group I All 4 pulmonary veins were successfully isolated in all 160 patients of Group I. Group II Even in Group II, all 4 pulmonary veins were successfully isolated in all 160 patients. In contrast, SVC isolation was performed in 134 of the 160 patients (84%). In 21 out of the remaining 26 patients, SVC isolation was not performed because of the risk of injury to the phrenic nerve, while in the remaining 5 patients because of lack of SVC potentials. The mean procedure time for the SVC isolation was 25 ± 10 minutes.

Procedure time and fluoroscopy time were, respectively, 2.5 ± 1.2 hours and 74 ± 23 minutes in Group I and 3.1 ± 1.4 hours and 91 ± 27 minutes in Group II. After 12 months of follow-up, 74% of patients (118/160) in Group I versus 81% (108/134) in Group II (P = ns) maintained sinus rhythm without AADs. Depending on the different type of AF, the success rate was 77% (56/73) versus 90% (55/61) in patients with paroxysmal AF (P = 0.04), 74% (30/41) versus 80% (27/34) in patients with persistent AF (P = ns) and 69% (32/46) versus 67% (26/39) in patients with permanent AF (P = ns) (Table 2). Data about patients that underwent a second procedure were not collected prospectively because this issue was not included in the initial intention of the study. However, data collected retrospectively showed that in the group of patients treated for paroxysmal AF with PVI only, 17 experienced

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Discussion

TABLE 1 Baseline Characteristics of the Study Population

Patients (n) Age (years) Gender (male/female) Type of AF Paroxysmal, n (%) Persistent, n (%) Permanent, n (%) Duration of AF (years) Left atrial diameter (mm) LVEF (%) HTN or SHD, n (%)

Main Findings

Group I (PVAI)

Group II (PVAI + SVCI)

P value

160 57 ± 9 118/42

134 55 ± 10 99/35

0.33 0.97

73 (46) 41 (26) 46 (28) 7.1 ± 4 4.6 ± 0.6 53 ± 7 101 (63)

61 (46) 34 (25) 39 (29) 6.5 ± 5 4.5 ± 0.8 54 ± 6 87 (65)

0.92 0.93 0.94 0.81 0.57 0.34 0.88

AF = atrial fibrillation; HTN = hypertension; LVEF = left ventricular ejection fraction; PVAI = pulmonary vein antrum isolation; SHD = structural heart disease; SVCI = superior vena cava isolation.

recurrences after the first ablation attempt. Four remained in sinus rhythm with AADs, 2 refused a second procedure, and 11 underwent a second ablation. Conduction was found to be restored in at least 1 PV in all 11 patients. During the second procedure, the empiric SVCI in addition to reisolation of the PV was performed in all patients. Spontaneous Ectopy from the SVC In accordance with the intention of the study, triggers arising from the SVC were not systematically investigated with provocative maneuvers such as isoproterenol iv. However, in the group of patients who underwent PVI + SVCI, spontaneous ectopy from the SVC was seen in 5 out of 160 patients (3.1%). In the group of patients who underwent PVI only, spontaneous ectopy from the SCV was not recorded. Procedural Complications Neither sinus node injury nor any injury to the phrenic nerve was observed in our series of ablation procedures. In addition, a CT scan performed at the third month of follow-up did not show any significant stenosis of the SVC. Five serious complications occurred in these series of patients (5/294 = 1.7%): 1 deep-vein thrombosis, 1 cerebrovascular accident, and 1 cardiac tamponade in the PVI alone group, and 1 severe pulmonary vein stenosis and 1 coronary artery embolism in the PVI + SVCI group (1.9% vs 1.5%; P = ns).

TABLE 2 Success Rate of Atrial Fibrillation Ablation

Patients (n) Total efficacy, n (%) Efficacy in Paroxysmal AF, n (%) Persistent AF, n (%) Permanent AF, n (%)

Group I (PVAI)

Group II (PVAI + SVCI)

P value and OR

160 118/160 (74)

134 108/134 (81)

0.16; 1.48

56/73 (77) 30/41 (74) 32/46 (69)

55/61 (90) 27/34 (80) 26/39 (67)

0.04; 2.78 0.52; 1.41 0.77; 0.88

AF = atrial fibrillation; OR = odds ratio; PVAI = pulmonary vein antrum isolation; SVCI = superior vena cava isolation.

To our knowledge, this is the first prospective randomized trial that has sought to establish the impact of the empiric and systematic SVCI in addition to PVAI in paroxysmal, persistent, and permanent AF. Our results revealed a significant difference in procedural success only in patients with paroxysmal atrial fibrillation. Comparison with Previous Studies The first evidence of PVs as the most frequent sites of triggers initiating AF was reported by Haissaguerre et al. in 1998.1 In the past 10 years, the different ablation strategies for the treatment of AF aimed at achieving complete PV electrical disconnection have reported an efficacy rate of 75-88%.3 The majority of ablation failure seems to be secondary to the restored conduction of PVs initially disconnected. However, reported cases of recurrences despite complete and persistent disconnection of PVs suggest an important role of non-PV triggers arising from different areas of the left and the right atrium. The SVC has been described as one of the most common sources of non-PV triggers. This is consistent with the embryologic origin of the SVC from “the sinus venous” (the same as sinoatrial node) that can explain the arrhythmogenic properties of this structure. Tsai et al. reported a 6% incidence of the SVC as a site of triggers for AF in a cohort of 130 patients.5 Subsequently, Lin et al. reported a greater incidence in a larger series of patients (11% in a series of 240 patients). The ablation of these triggers resulted in an efficacy rate of 87% after longterm follow-up.6 Usually, the ablation of these sites is considered only if firing is observed during the ablation procedure. Interestingly, in the study of Lin et al., only 7% of these foci were observed spontaneously during the procedure, while 93% of the firings were discovered following isoproterenol infusion or immediately after cardioversion. This suggests that most triggers arising from the SVC could be missed without the use of provocative maneuvers. Arruda et al. described an incidence of 12% of SVC triggers in a cohort of 190 patients.11 If the firings were present (recorded spontaneously or induced during isoproterenol infusion) SVCI was performed. A repeat procedure in a small number of patients of this group with recurrences of AF showed an adjunctive rate of 2% of firings arising from the SVC that were not identified during the first attempt of ablation. In contrast, the authors found a significantly lower number of firings arising from the SVC (0.4%) in a subsequent group of patients who had been empirically and systematically treated with SVCI. Therefore, it is possible that shifting from the ablation of SVC triggers only if identifiable during the procedure to systematic SVCI could result in a greater efficacy of ablation. This hypothesis was not confirmed in the randomized study recently published by Wang et al.12 in which authors did not find any significant difference on the outcome of 106 paroxysmal AF ablation treated with SVCI or not. However, in this study the reported incidence of SVC-originated arrhythmias was much lower than that reported in the literature

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(3.7%), and it is likely that in such a small series of patients, this fact could have affected the results. In contrast, our percent of incremental benefit of systematic SCVI in paroxysmal AF ablation resulted very near to the reported frequency of trigger arising from the SVC in the study of Lin et al. (11%) and in the study of Arruda et al. (12%). It is also important to note that, in the case of a redo procedure, the SVC was observed to be always persistently isolated. Therefore, almost the entire benefit of the SCVI is obtained just after the first attempt of ablation. The fact that in our prospective randomized study the systematic SVCI has significantly improved the efficacy of AF ablation only in patients with paroxysmal AF is consistent with the emerging idea that solely the ablation of triggers is more effective in paroxysmal than in permanent AF. On the other hand, a better outcome of persistent and permanent AF ablation requires a more extensive ablation of the substrate that certainly cannot be obtained only with SCVI. After these considerations, it is difficult to offer any other possible explanation for the results observed in our study out of the simple ablation of triggers. However, it is an interesting observation of Arruda et al. that firing arising from the SCV is always associated with firing arising from the right superior pulmonary vein. Therefore, we cannot exclude that the ablation of the SVC could in some way complete the isolation of the right superior pulmonary vein or could create a modification of the substrate on the right side of the septum that is helpful for the success of ablation. However, considering the limited incremental benefit of SCVI reported by our and previous studies, larger series of patients are necessary to confirm these findings. Study Limitations We cannot exclude that with a larger sample size, a statistically significant difference could have been discovered also in patients with persistent or permanent AF. However, our study suggests that the major benefit of SVCI is obtained in the group of patients treated for paroxysmal AF. It is also important to note that we did not perform a systematic research of asymptomatic episodes of AF by means of prolonged (7 days) Holter monitoring or daily electrocardiographic transtelephonic transmission. However, this limitation applies to both study groups. So it is likely that it has not influenced the outcome results. The last limitation of the study is that it was designed to evaluate whether SVCI in addition to PVI is superior to PVI alone after a single ablation procedure. Therefore, the study findings do not show adequate evidence to support the strategy of SVCI in addition to PVI in every patient with PAF.

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Conclusion In our study, the strategy of empiric SVCI in addition to PVAI has improved the outcome of AF ablation solely in patients manifesting paroxysmal AF. References 1. Haissaguerre M, Jais P, Shah DC, Takahashi A, Honcini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, Clementy J: Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659-666. 2. Chen SA, Hsieh MH, Tai CT, Tsai CF, Prakash VS, Yu WC, Hsu TL, Ding YA, Chang MS: Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: Electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 1999;100:1879-1886. 3. Verma A, Natale A: Should atrial fibrillation ablation be considered first line therapy for some patients? Why atrial fibrillation ablation should be considered first-line therapy for some patients. Circulation 2005;112:1214-1222. 4. Natale A, Raviele A, Arentz T, Calkins H, Chen SA, Haissaguerre M, Hindricks G, Ho Y, Kuck KH, Marchlinski F, Napolitano C, Packer D, Pappone C, Prystowsky EN, Schilling R, Shah D, Themistoclakis S, Verma A: Venice chart international consensus document on atrial fibrillation ablation. J Cardiovasc Elecrophysiol 2007;18:560580. 5. Tsai CF, Tai CT, Hsieh MH, Lin WS, Yu WC, Ueng KC, Ding YA, Chang MS, Chen SA: Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava. Circulation 2000;102:6774. 6. Lin WS, Tai CT, Hsieh MH, Tsai CF, Lin YK, Tsao HM, Huang JL, Yu WC, Yang SP, Ding YA, Chang MS, Chen SA: Catheter ablation of paroxysmal atrial fibrillation initiating by non-pulmonary vein ectopy. Circulation 2003;107:3276-3283. 7. Hwang C, Wu TJ, Doshi RN, Peter CT, Chen PS: Vein of Marshal cannulation for the analysis of electrical activity in patients with focal atrial fibrillation. Circulation 2000;101:1503-1505. 8. Hsu LF, Ja¨ıs P, Keane D, Wharton JM, Deisenhofer I, Hocini M, Shah DC, Sanders P, Scav´ee C, Weerasooriya R, Cl´ementy J, Ha¨ıssaguerre M: Atrial fibrillation originating from persistent left superior vena cava. Circulation 2004;109:828-832. 9. Sanders P, Ja¨ıs P, Hocini M, Ha¨ıssaguerre M: Electrical disconnection of the coronary sinus by radiofrequency catheter ablation to isolate a trigger of atrial fibrillation. J Cardiovasc Electrophysiol 2004;15:364368. 10. Themistoclakis S, Schweikert RA, Saliba WI, Bonso A, Rossillo A, Bader G, Wazni O, Burkhardt DJ, Raviele A, Natale A: Clinical predictors and relationship between early and late atrial tachyarrhythmias after pulmonary vein antrum isolation. Heart Rhythm 2008;5:679685. 11. Arruda M, Mlcochova H, Prasad SK, Kilicaslan F, Saliba W, Patel D, Fahmy T, Morales LS, Schweikert R, Martin D, Burkhardt D, Cummings J, Bhargava M, Dresing T, Wazni O, Kanj M, Natale A: Electrical isolation of the superior vena cava: An adjunctive strategy to pulmonary vein antrum isolation improving the outcome of AF ablation. J Cardiovasc Electrophysiol 2007;18:1261-1266. 12. Wang XH, Liu X, Sun YM, Shi HF, Zhou L, Gu JN: Pulmonary vein isolation combined with superior vena cava isolation for atrial fibrillation ablation: A prospective randomized study. Europace 2008;10:600-605.